The n e w e ng l a n d j o u r na l of m e dic i n e

Clinical Practice

Caren G. Solomon, M.D., M.P.H., Editor

Chronic Pancreatitis
Santhi Swaroop Vege, M.D., and Suresh T. Chari, M.D.​​

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence
­supporting various strategies is then presented, followed by a review of formal guidelines, when they exist.
The article ends with the authors’ clinical recommendations.

A 52-year-old man reports having had two to three episodes of acute pancreatitis From the Division of Gastroenterology
each year for the past 6 years. During the past 6 months, debilitating, continuous and Hepatology, Mayo Clinic, Rochester,
MN (S.S.V.); and the Department of Gas-
upper abdominal pain has gradually developed despite escalating treatment with troenterology, Hepatology, and Nutrition,
meloxicam, tramadol, and, recently, oxycodone. He has three to four bulky, foul- Division of Internal Medicine, University
smelling stools daily; he reports no weight loss. He has a 20-year history of alcohol of Texas M.D. Anderson Cancer Center,
Houston (S.T.C.). Dr. Chari can be con-
use and a 25 pack-year smoking history. He has left his position at a company owing tacted at ­stchari@​­mdanderson​.­org or at
to frequent absences. Computed tomography of the abdomen reveals scattered pan- the Department of Gastroenterology,
creatic ductal calcifications, a dilated pancreatic duct, and an atrophic pancreas. Hepatology and Nutrition, Division of In-
ternal Medicine, University of Texas M.D.
How would you manage this case? Anderson Cancer Center, 1515 Holcombe
Blvd., Houston, TX 77030.

The Cl inic a l Probl em N Engl J Med 2022;386:869-78.

C
DOI: 10.1056/NEJMcp1809396
hronic pancreatitis is a progressive fibroinflammatory dis- Copyright © 2022 Massachusetts Medical Society.

ease. Classic chronic pancreatitis, usually associated with alcohol use, CME
smoking, or certain gene mutations,1 typically begins with recurrent pain- at NEJM.org
ful bouts of pancreatitis, followed by the insidious development of chronic, de-
bilitating pain during the next 3 to 5 years after an initial episode. Classic imaging
findings of one or more of the triad of pancreatic ductal calcifications, ductal
dilatation, and parenchymal atrophy indicate progression to chronic pancreatitis.
A substantive subgroup of patients also classified as having chronic pancreatitis
have neither pain (nearly 30%)2 nor a previous diagnosis of acute pancreatitis (ap-
proximately 50%).3 The primary form without pain or previous acute pancreatitis
may be a different disease with a distinct pathogenesis.3 In practice, “chronic
pancreatitis” is often used with a qualifier to describe other chronic inflamma-
An audio version
tory diseases of the pancreas (Table S1 in the Supplementary Appendix, available
of this article
with the full text of this article at NEJM.org), which share some, but not all, of the is available at
characteristic features of classic chronic pancreatitis.4 This general overview is NEJM.org
focused only on classic chronic pancreatitis in adults.
The annual incidence of chronic pancreatitis in the United States ranges from
5 to 8 per 100,000 adults, and the prevalence ranges from 42 to 73 per 100,000
adults.5 Risk factors include alcohol use (in 42 to 77% of patients), smoking (in
>60%), and genetic mutations (in 10%); the disease is considered to be idiopathic
in 28% of patients.5 Alcohol use (>80 g per day for 6 to 12 years1) and smoking
(a smoking history of >35 pack-years increases the risk of chronic pancreatitis by
a factor of 51,5) have synergistic effects.1,5 Two thirds of patients with chronic pan-
creatitis are men, and risk is higher among Black persons than among White
persons.5 Genetic mutations most commonly involve cystic fibrosis transmem-
brane conductance regulator (CFTR), serine protease inhibitor Kazal type1 (SPINK1),

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Key Clinical Points

Chronic Pancreatitis
• Chronic pancreatitis, which is commonly associated with alcohol use, smoking, or genetic risk factors,
often manifests as recurrent bouts of abdominal pain or pancreatitis. Characteristic imaging findings
include pancreatic stones, dilated ducts, and atrophy.
• Complications of chronic pancreatitis include pseudocysts, biliary strictures, exocrine and endocrine
pancreatic insufficiency, bone loss, and pancreatic cancer; there is currently no effective early detection
strategy for pancreatic cancer.
• Exocrine insufficiency causing steatorrhea leads to weight loss, sarcopenia, and deficiencies of fat-
soluble vitamins and other micronutrients and is mitigated by treatment with pancreatic-enzyme
replacement.
• Strategies for managing chronic abdominal pain include medical therapies (analgesic agents, limited
use of narcotics, antioxidants, and neuromodulators), endoscopic treatment (pancreatic stenting
with or without extracorporeal shockwave lithotripsy), and surgical interventions (duct drainage and
resection procedures), as well as behavioral interventions for centrally mediated pain.

or chymotrypsin C (CTRC); more than 90% of
these cases manifest as apparently sporadic
early-onset (<35 years of age) pancreatitis.4 Heredi-
tary pancreatitis, a rare autosomal dominant
disease caused by cationic trypsinogen (PRSS1)
gene mutation, accounts for approximately 1%
of all cases.5 Regardless of the cause, chronic
pancreatitis confers a predisposition to pancreatic
cancer. The cumulative risk is 1.8% at 10 years
and 4% at 20 years of follow-up among patients
with sporadic chronic pancreatitis and 7.2% by
70 years of age among those with hereditary
pancreatitis.5,6
Approximately 70% of patients present with
episodic upper abdominal pain, nausea, and
vomiting. Pain patterns include intermittent
severe attacks with or without pancreatitis that
occur early in the course of disease (type A),
persistent chronic pain between intermittent
severe attacks (type B), and chronic severe pain
without severe attacks (type C), which is the
most debilitating pain pattern (Table 1). Chronic
pain is attributed to peripheral and central neu-
ral sensitization7-9 that results in visceral sensi-
tivity, allodynia (pain elicited by a stimulus that
normally does not produce pain), and hyperalge-
sia. Severe disabling pain that warrants narcotic
use disrupts patients’ lives, with consequences
often compounded by alcohol use and psychoso-
cial factors, such as poor resilience and inade-
quate social support.
Complications of chronic pancreatitis include
pseudocysts, bile-duct stricture, duodenal stric-
ture, splanchnic venous thromboses, and pan-
creatic cancer. Loss of islet mass and insulin
causes glucose intolerance and eventually diabe-
tes (type 3c)10; loss of counterregulatory hor-
mones can cause wide swings in blood glucose
levels. Exocrine pancreatic dysfunction can prog-
ress from a “pancreas sufficient” phase (stage I
or II) to pancreatic exocrine insufficiency char-
acterized by steatorrhea (stage III or IV)11; pan-
creatic exocrine insufficiency occurs with near
total (>90%) loss of pancreatic exocrine func-
tion. Prolonged steatorrhea leads to weight loss,
sarcopenia (decreased muscle mass), and defi-
ciencies of fat-soluble vitamins (A, D, E, and K),
vitamin B12, and other micronutrients (zinc and
magnesium)1,12 (stage IV11). The chronic inflam-
matory state and deficiency of vitamin D and
possibly vitamin K often result in osteopenia or
osteoporosis, with bone pain and low-impact
fractures.13,14 Chronic pancreatitis is associated
with increased mortality from any cause.15
S t r ategie s a nd E v idence
Evaluation and Diagnosis
Evaluation for chronic pancreatitis and its com-
plications includes a careful clinical history tak-
ing, laboratory testing, and imaging. Histologic
analysis (Fig. S1) is not needed for diagnosis and
is often not available; definitive diagnosis rests
heavily on imaging findings. Laboratory testing
includes assessment of pancreatic endocrine
function (screening for diabetes mellitus) and
exocrine function (described below).
Imaging
Imaging methods include computed tomography
(CT) (Fig. 1), magnetic resonance cholangiopan-
creatography (MRCP), and endoscopic ultrasonog-

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 Clinical Pr actice

Table 1. Suggested Assessments for Impairments in Biophysical Domains.

Domain and Assessment Categorization

Pain: duration since onset, intermittent or continuous,
frequency of flares, severity during and between
flares on visual analogue scale, documentation of
pancreatitis during flares (serum lipase or imaging
evidence), relationship of pain to activities such as
eating and exercise, response to treatments, and
use and frequency of narcotics and side effects
(constipation, bloating, and increased pain)
Imaging: evidence on CT, MRI, or endoscopic ultrasonog- Examples: strictures, stones, pseudocyst, or dilated pancre-
raphy of amenability to endoscopic intervention or
surgical drainage
Pancreatic exocrine function*
Symptoms of steatorrhea
Fecal elastase level
Fecal fat test over period of 48 or 72 hr
Serum fat-soluble vitamins (A and E) and other micro-
nutrients (zinc, magnesium, and vitamin B12)
Malnutrition: hand grip, body-mass index, unplanned
weight loss, and bone density†
Pain patterns: type A is intermittent attacks of pain or pan-
creatitis without intervening pain; type B is intermittent
attacks of pain or pancreatitis with intervening pain for
which narcotics are not used (type B1), for which nar­
cotics are used for ≤6 mo (type B2), or for which narcot-
ics are used for >6 mo (type B3) (centrally mediated
abdominal pain syndrome7); and type C is continuous
narcotic-treated pain for >6 mo without intermittent
attacks of pain or acute pancreatitis or complications
(centrally mediated abdominal pain syndrome7)
atic duct
Classic symptoms, suggestive but not diagnostic symptoms,
or no symptoms
Generally <50 μg per gram of stool in stage III or IV
>7 g per day in stage III or IV
Vitamin and micronutrient deficiency: present or absent
Muscle wasting (none, mild, moderate, or severe), muscle
strength (normal or impaired), and osteoporosis or
­osteopenia: present or absent‡

* Treatment with pancreatic-enzyme replacement is appropriate if one or more of the following is present: classic symp-
toms of steatorrhea (bulky, foul-smelling, difficult-to-flush stools with weight loss); suggestive symptoms plus a fecal
elastase level of less than 50 μg per gram of stool or low micronutrient levels; or a fecal fat level of 15 g or more per day.
† The Malnutrition Universal Screening Tool calculator can be used to establish nutritional risk with the use of either ob-
jective measurements of height and weight to obtain a score and a risk category or subjective criteria to estimate a risk
category but not a score. The “Timed Up and Go (TUG)” instrument can be used for assessing fall risk (https://www​
.­cdc​.­gov/​­steadi/​­pdf/​­TUG_test​-­print​.­pdf).
‡ Interventions include strength training and nutritional supplementation.

raphy (EUS); endoscopic retrograde cholangiopan- Other Evaluations

creatography (ERCP) is no longer recommended
owing to complications and the availability of
noninvasive imaging.1 Of these, CT is the most
readily available and widely used. In a large
meta-analysis, the sensitivity and specificity of
CT, magnetic resonance imaging (MRI), and
EUS did not differ significantly,16 but EUS is in-
vasive, observer-dependent, and prone to false
positive results.
MRCP, especially after secretin stimulation,
has the advantages of better delineation of the
pancreatic and bile ducts, the absence of radia-
tion, and safety in patients with allergy to con-
trast media or with renal insufficiency with the
use of noncontrast T2-weighted sequences.
However, MRCP takes longer and is more ex-
pensive than CT or MRI, is unsuitable for pa-
tients with claustrophobia, and can miss calci-
fication.17
Assessment of multiple domains (Tables 1 and
2) is warranted, including the nature and sever-
ity of upper abdominal pain, imaging findings,
nutritional status, substance abuse, disability
due to disease, resilience and motivation for
behavioral change, and effect of the disease on
psychosocial function. Pancreatic exocrine func-
tion is evaluated by history taking and labora-
tory testing. Individual symptoms (abdominal
pain, diarrhea, and bulky, foul-smelling, difficult-
to-flush, pale, or oily stools) are neither sensitive
nor specific for steatorrhea; however, a reduction
in symptoms with pancreatic-enzyme replace-
ment strongly supports steatorrhea.23 Persistent
steatorrhea is associated with weight loss and
micronutrient deficiencies. In the absence of a
classic symptom complex, exocrine function
should be assessed by fecal elastase-1 measured
in a single stool sample and, when indicated,

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

C D

Figure 1. Examples of Imaging Findings and Suggested Interventions in Painful Chronic Pancreatitis.
In Panel A, CT shows multiple calcifications (long arrow) with a dilated pancreatic duct (short arrows). Possible
interventions include duodenum-preserving resection of the head of the pancreas (Beger procedure), coring of the
pancreatic head with pancreaticojejunostomy (Frey procedure), or pancreaticojejunostomy (Partington–Rochelle
procedure). In Panel B, CT shows a single 1-cm stone in a pancreatic duct (long arrow) and upstream dilatation
of the duct (short arrow). Possible interventions include extracorporeal shockwave lithotripsy with clearance of the
pancreatic duct by means of endoscopic retrograde cholangiopancreatography or pancreaticojejunostomy (Parting-
ton–Rochelle procedure). In Panel C, magnetic resonance cholangiopancreatography shows a stricture of the main
pancreatic duct (arrow). A possible intervention is endoscopic stenting with intermittent exchanges for 1 year. In
Panel D, CT shows a mass in the head of the pancreas (within circle). Possible interventions include duodenum-
preserving resection of the head of the pancreas (Beger procedure), pancreaticoduodenectomy (Whipple procedure),
or coring of the pancreatic head with pancreaticojejunostomy (Frey procedure).

quantitative fecal fat measured in stool collected
over a period of 48 to 72 hours while the patient
follows a diet containing 100 g of fat daily.
Measurement of the fecal elastase level is
simple, inexpensive, and widely available. Levels
below 200 μg per gram of stool are considered
to be abnormal, but only very low values (≤50 μg
per gram or even <15 μg per gram, according to
one report24) are reasonably predictive of steator-
rhea.25,26 Abnormal levels above 50 μg per gram
occur in many other conditions, including dia-
betes, old age, irritable bowel syndrome, inflam-
matory bowel disease, renal failure, functional
dyspepsia, and any watery diarrhea26 and have
poor specificity for steatorrhea. The frequent
mischaracterization of any abnormality in fecal
elastase levels as pancreatic insufficiency has led
to overdiagnosis and overtreatment.
Quantitative fecal fat testing is available
through many academic centers and major refer-
ence laboratories in the United States. Chal-
lenges to its routine use include patient adher-
ence to the recommended diet, complete stool
collection, and cumbersome manual laboratory
testing and analysis. With proper instructions
and adherence to the 100-g fat diet for 2 days
before and throughout the stool-collection period,
fecal fat testing provides the best estimate of di-
gestive capacity. A normal value for the coeffi-
cient of fat absorption is at least 93%, and a
normal amount of fat in stool is less than 7 g per
24 hours; elevated values occur in disorders of
absorption and digestion.
In routine clinical practice, a fecal elastase
test can be performed annually as a screening
test for pancreatic exocrine insufficiency. A fecal
fat test should be performed to confirm pancre-
atic insufficiency if fecal elastase levels or vitamin

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 Clinical Pr actice

Table 2. Suggested Assessments and Interventions for Impairments in Psychosocial Domains.

Domain Assessment* Categorization Intervention†

Disability due Functional impairment at home, work, Disability: none, mild, moderate, Options include cognitive behavioral therapy,
to disease school, or in other social areas18 severe, or extreme resilience training, and formal pain rehabili-
tation programs
Substance use Use of tobacco, alcohol, prescription Addictions: present or absent; if Encourage patient to seek help from addiction
disorders medication, and other substances19 present, to which substances clinics
Resilience Ability to bounce back from setbacks20 Resilience: low, normal, or high If resilience is impaired, recommend referral to
stress management and resilience training
program
Motivation Motivation to initiate or maintain Motivation: low (not interested), For type B or C pain patterns, introduce pa-
­behavior changes21 moderate (skeptical but will- tients to and encourage participation in
ing to engage), or high (be- nonstructural interventions
lieves in and wants help)
Social support Quality of social relationships22 Social support: low, moderate, If social support is low, refer patient to social
or high worker

* Assessments can be performed at bedside in all patients, especially those with pain patterns type B and C. Validated questionnaires include
the World Health Organization Disability Assessment Schedule 2.018; Tobacco, Alcohol, Prescription Medication, and Other Substance Use
(TAPS) Tool19; Brief Resilience Scale20; Motivation and Attitudes toward Changing Health (MATCH) scale21; and Multidimensional Scale of
Perceived Social Support.22
† The integrated (holistic) management of patients with impairments in multiple biophysical and psychosocial domains may require referral
to tertiary care centers.

A or E levels are very low in the absence of the pancreatectomy,29 particularly among those with
classic complex of symptoms of steatorrhea. prolonged preoperative narcotic use and alco-
holic and nonhereditary pancreatitis.
Management There is no effective medical treatment to
Indications for treatment in patients with chron- stop the recurrence of acute pancreatitis. For
ic pancreatitis are pain, complications, and func- acute and chronic pain, medical therapies in-
tional (endocrine and exocrine) insufficiency. clude analgesic agents, antioxidants, and neuro-
Treatment options are described below. modulators (e.g., gabapentinoids and tricyclic
antidepressants)1,5,9,30-32 (Table 3). Regular use of
Pain opioids should be avoided owing to risks of tol-
Management of pain in patients with chronic erance, addiction, narcotic bowel syndrome, and
pancreatitis has traditionally relied on the bio- a paradoxical increase in pain due to opioid-
physical model of health and disease, which induced hyperalgesia. Two meta-analyses of ran-
posits that all symptoms have a structural basis. domized trials of various commercially available
However, recognition of central sensitization antioxidant combinations (vitamins A, C, and E
and the role of psychological and social factors and S-adenosyl-methionine) have shown signifi-
associated with chronic pain support expansion cant reductions in the number of days with pain
of management approaches to include attention and in narcotic use.33,34 However, the trials in-
to nonstructural behavioral interventions.27,28 cluded small numbers of patients, and one trial
Management of pain starts with developing showed no benefit; the recommendation to use
a strong patient–physician rapport and acknowl- these is based on potential benefits and the ab-
edging patients’ pain and disability. Patients sence of adverse effects. Short-term placebo-
should be educated about both structural and controlled trials have shown reductions in pain
nonstructural interventions (Fig. 2). The latter are among patients with chronic pancreatitis with
particularly important for patients with centrally pregabalin alone31 or in combination with anti-
mediated abdominal pain syndrome and impair- oxidants.35 Other neuromodulators, such as gaba-
ments in nonstructural domains; this is sup- pentin, tricyclic antidepressants, and serotonin–
ported by evidence of a high incidence of ongo- norepinephrine reuptake inhibitors, have also
ing long-term narcotic use (>40%) for abdominal been suggested as possible treatments, but ran-
pain among patents who have undergone total domized trials of their use specifically for pan-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Establish physician–patient rapport

Assess biophysical and psychosocial impairments

Pain pattern Psychosocial impairments

Type A Type B Type C

Intermittent, infrequent Intermittent severe Severe, constant pain without
attacks of pain or pancreatitis pain with continuous attacks of pain or pancreatitis
pain between attacks

Structural intervention based
on imaging
Consider no structural
intervention in infrequent
attacks (>1 yr apart)
Structural intervention
(endoscopic and structural)
based on imaging
For pain warranting narcotics,
consider medical and
behavioral or psychosocial
interventions in tandem or
sequentially with structural
intervention
Structural intervention may
be wholly or largely unsuc-
cessful
Strongly emphasize nonstruc-
tural interventions
Behavioral and psychosocial
interventions
Offer referral to one or
more:
Addiction clinic
Psychologist for cognitive
behavioral therapy
Pain rehabilitation
through integrated
behavioral, physical,
and occupational
therapies
Stress management and
resilience training
Social worker in case of
poor social support

Figure 2. An Integrated Approach to Biophysical and Psychosocial Impairments.

creatitis-associated pain are lacking.42 Although
pancreatic enzymes can alleviate symptoms of
maldigestion, a systematic review and meta-
analysis showed no evidence of benefit for pan-
creatic pain.36
Endoscopic Therapy
Endoscopic therapy, predominantly involving the
removal of stones in a pancreatic duct, dilatation
of strictures, or both, is often the first interven-
tion43 for moderate-to-severe pain (types A, B1,
and B2) that does not respond to medical thera-
py. Extracorporeal shockwave lithotripsy is used
for breaking up stones, either as a stand-alone
therapy (for stones <5 mm in diameter) or as an
adjunct to ERCP44 (Fig. 1). For strictures in a
pancreatic duct, prolonged dilatation (of approxi-
mately 1 year) with the use of 10 French plastic
stents, with intermittent stent exchanges, is
generally warranted; pain relief is reported in
more than 70% of patients.43 Endoscopic man-
agement is also indicated for some complica-
tions of chronic pancreatitis (e.g., pseudocysts
and pancreatic ascites).
Surgery
Options for surgery for pain relief include pan-
creatic resection for persistent focal inflamma-
tion (standard pancreaticoduodenectomy and its
variants or distal pancreatectomy), drainage of
an obstructed duct (longitudinal pancreaticojeju-
nostomy and its variants), or a combination of
both (Frey procedure)45-47 or, in the most refrac-
tory cases, total pancreatectomy with or without

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 Clinical Pr actice

Table 3. Interventions for Pain in Chronic Pancreatitis.*

Intervention Indications Comments

Analgesics: NSAIDs, tramadol,
and opioids
Neuromodulators
Antioxidants: vitamins A, C, and
E, selenium, and methionine
Treatment with pancreatic-
enzyme replacement
Pain procedures: celiac plexus
block, spinal cord stimula-
tion, and acupuncture
Addiction treatment, counseling, Neuropathic pain, along with Abstinence from alcohol may protect against recurrence of attacks, slow
and psychosocial interven-
tions (cognitive behavioral
therapy, stress management
and resilience training, and
pain rehabilitation)
Initial treatment Use WHO pain ladder (for mild pain, nonopioid analgesics; for moderate
pain, weak opioids; and for severe pain, potent opioids with nonste-
roidal agents, the adjuvants listed below, or both); consider alternate
interventions if opioids are used continuously
Within months after narcotic Can be used along with structural therapies; pregabalin superior to pla-
use, neuropathic pain cebo in randomized, controlled trial31; gabapentin and selective epi-
nephrine or norepinephrine reuptake inhibitors also recommended by
experts
At any stage to reduce painful Reduced pain in meta-analyses of randomized trials of supplements33,34
attacks as well as days (although trials were small, and one showed no benefit); randomized
with pain trial showed benefit in combination with neuromodulators35; can be
combined with any intervention; generally given as fixed-dose combina-
tion; increased intake from dietary sources may be encouraged but has
not been formally studied
Reduce bloating, cramping, Meta-analyses show no benefit for pain relief36
and borborygmi
Neuropathic pain, usually Evidence limited for acupuncture,37 spinal cord stimulation,38 and celiac
after endoscopic and sur- plexus block9
gical interventions, if no
relief
or after endoscopic or deterioration of pancreatic function, and reduce mortality39; random-
surgical interventions ized, controlled trial showed benefit of Internet-based cognitive behav-
ioral therapy40; psychosocial or behavioral therapy effective for chronic
pain41 and useful for motivated patients, especially those with clinically
significant disability from disease, addictions, or poor resilience

* NSAIDs denotes nonsteroidal antiinflammatory drugs, and WHO World Health Organization.

autologous islet-cell transplantation45,48 (Fig. 1). change the way patients think about and cope
Complications of chronic pancreatitis, such as with pain); stress management and resilience
biliary entrapment or pancreatic cancer, are ad- training (to reduce anxiety and improve coping
ditional indications for surgery. For best results, skills); dedicated pain rehabilitation programs
it is important to consider surgery before the that incorporate behavioral, physical, and occu-
development of opioid dependence and neuro- pational therapies; and treatment of addictions
pathic pain.8,42,47 (nicotine, alcohol, and narcotics) (Table 2). On
Three randomized trials have compared sur- the basis of studies of the management of
gery with endoscopic therapy for painful chronic chronic pain in other contexts51 and of clinical
pancreatitis46,49,50; all showed higher percentages experience with patients with chronic pancreati-
of patients having pain relief with surgery than tis, these interventions improve functional status
with endoscopy (34 to 78% vs. 15 to 39%), with and psychosocial well-being. A recent random-
similar complication rates and mortality and a ized, controlled trial showed efficacy of Internet-
greater use of reinterventions in the endoscopy based cognitive behavioral therapy for pain in
group. Because endoscopic intervention is less patients with chronic pancreatitis.40
invasive and does not preclude subsequent sur-
gery, it is typically preferred as the initial option. Exocrine Pancreatic Insufficiency
However, patients with persistence of pain de- Treatment with pancreatic-enzyme replacement
spite endoscopic therapy should be reevaluated mitigates the effects of steatorrhea.12 It is indicated
for surgery and nonstructural interventions (Fig. 1).
if a patient has one or more of the following:
classic symptoms of steatorrhea; suggestive but
Nonstructural Interventions not diagnostic symptoms plus a fecal elastase
Important adjuvants to structural interventions level of less than 50 μg per gram of stool or low
include cognitive behavioral therapy (to help micronutrient levels; or a fecal fat level of 15 g

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 The n e w e ng l a n d j o u r na l
or more per day. All Food and Drug Administra-
tion–approved enzyme products are of porcine
origin, and most are coated to delay degradation
by gastric acid.52 Although enzyme therapy (usual
starting dose, 20,000 to 50,000 U.S. Pharmaco-
peia units of lipase activity) generally does not
abolish steatorrhea (mean coefficient of fat ab-
sorption during enzyme therapy, approximately
85%),52 it reduces symptoms and ameliorates
nutritional deficiencies. Many factors influence
the efficacy of enzymes, including the caloric
and fat content of the diet, secretion of gastric
acid, gastric emptying, altered anatomy, variable
increase in extrapancreatic lipolysis, and bacterial
overgrowth in the small bowel. The effectiveness
of enzyme therapy may be increased by taking the
enzymes with meals (distributed throughout the
meal), distributing dietary calories across four
or five meals per day, using acid-reducing agents,
and testing and treating for bacterial overgrowth
in the small bowel. Dietary fat restriction should
be avoided to prevent weight loss and deficiency
of fat-soluble vitamins and essential fatty acids.53
Pancreatic Cancer
There is no effective screening strategy for early
detection of pancreatic cancer in patients with
chronic pancreatitis. In patients with hereditary
chronic pancreatitis, alternating MRI and EUS
have been recommended for screening without
evidence of effectiveness or improved outcomes.6
Carbohydrate antigen 19-9, the best known sero-
logic marker of pancreatic cancer, may be falsely
elevated in patients with chronic pancreatitis
and is not helpful for screening.
A r e a s of Uncer ta in t y
Further study is needed of strategies for early
detection of chronic pancreatitis,54 prevention of
recurrent pancreatitis and its progression, iden-
tification and assessment of centrally mediated
chronic neuropathic pain, identification of pan-
creatitis-related diabetes (type 3c) as compared
with other causes of diabetes, and early detec-
tion of pancreatic cancer. The natural history of
chronic pancreatitis is not well understood but
is currently being studied in a prospective cohort
study in the United States (Prospective Evalua-
tion of Chronic Pancreatitis for Epidemiologic
and Translational Studies [PROCEED]).55 The
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of m e dic i n e
relationship between exocrine and endocrine dys-
function (type 3c diabetes) in chronic pancreati-
tis and the role of newer diabetes therapies in
treating type 3c diabetes are uncertain. Larger
and longer-term trials are needed to better as-
sess pharmacologic, behavioral, and structural
interventions for chronic pain (particularly neuro-
pathic type) associated with chronic pancreatitis.
Guidel ine s
Several guidelines have been published in the
past 5 years (Table S2), some involving overall
evaluation and management and others focused
on one specific aspect of the disease. The recom-
mendations in this article are generally consis-
tent with these guidelines, except that guide-
lines have not addressed the evaluation and
management of psychosocial domains contribut-
ing to chronic pain.
C onclusions a nd
R ec om mendat ions
The patient in the vignette has chronic pancre-
atitis associated with alcohol and smoking, with
both centrally mediated and pancreatitis-related
pain (type B2). His history also suggests exo-
crine pancreatic insufficiency; confirmation with
fecal elastase or fecal fat testing is recommend-
ed. We would assess levels of fat-soluble vitamins,
zinc, magnesium, vitamin B12, and glycated hemo-
globin and consider baseline dual-energy x-ray
absorptiometry. If pancreatic insufficiency is con-
firmed, we would treat with pancreatic-enzyme
replacement and a balanced diet supplemented
with fat-soluble vitamins and micronutrients and
with normal fat content. For his chronic pain,
structural as well as nonstructural interventions
will probably be necessary. Given the presence of
stones of more than 5 mm in diameter, extracor-
poreal shockwave lithotripsy would be appropri-
ate, with or without ERCP (if a stricture in a
pancreatic duct is present) to clear the frag-
ments, with a plan for surgical intervention if
pain persists. For further management of ongo-
ing pain, we would recommend pregabalin along
with referral to a pain rehabilitation program,
where available, including cognitive behavioral
therapy. Counseling regarding alcohol, nicotine,
and narcotic use; stress management; and resil-
nejm.org March 3, 2022

ience training are important. Periodic follow-up,
initially at intervals of 6 months or 1 year, will
be needed to evaluate the effectiveness of treat-
ment and disease progression.
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Clinical Pr actice
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